Open AccessPotent and Selective Human Prostaglandin F (FP) Receptor Antagonist (BAY-6672) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)
Author(s) -
Hartmut Beck,
Tobias Thaler,
Daniel Meibom,
Mark Meininghaus,
Hannah Jörißen,
Lisa Dietz,
Carsten Terjung,
M. Bairlein,
Clemens-Jeremias von Bühler,
Sonja Anlauf,
Chantal Fürstner,
Timo Stellfeld,
Dirk Schneider,
Kersten M. Gericke,
Thomas Buyck,
Kai Lovis,
Uwe Münster,
Johanna Anlahr,
Elisabeth Kersten,
Guillaume Levilain,
Virginia Marossek,
Raimund Kast
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00834
Subject(s) - idiopathic pulmonary fibrosis , pirfenidone , nintedanib , antagonist , pharmacology , in vivo , lung , fibrosis , pulmonary fibrosis , prostaglandin , bioavailability , receptor antagonist , chemistry , medicine , receptor , biology , microbiology and biotechnology
Idiopathic pulmonary fibrosis (IPF) is a rare and devastating chronic lung disease of unknown etiology. Despite the approved treatment options nintedanib and pirfenidone, the medical need for a safe and well-tolerated antifibrotic treatment of IPF remains high. The human prostaglandin F receptor (hFP-R) is widely expressed in the lung tissue and constitutes an attractive target for the treatment of fibrotic lung diseases. Herein, we present our research toward novel quinoline-based hFP-R antagonists, including synthesis and detailed structure-activity relationship (SAR). Starting from a high-throughput screening (HTS) hit of our corporate compound library, multiple parameter improvements-including increase of the relative oral bioavailability F rel from 3 to ≥100%-led to a highly potent and selective hFP-R antagonist with complete oral absorption from suspension. BAY-6672 ( 46 ) represents-to the best of our knowledge-the first reported FP-R antagonist to demonstrate in vivo efficacy in a preclinical animal model of lung fibrosis, thus paving the way for a new treatment option in IPF.